tbuckley/cabot-search huggingface dataset:
Use of Bayesian Statistics to Reanalyze Data From the Pragmatic Randomized Optimal Platelet and Plasma Ratios Trial
Authors: Daniel Lammers, Joshua Richman, John B. Holcomb, Jan O. Jansen
Journal: JAMA Network Open (2023)

Importance Frequentist statistical approaches are the most common strategies for clinical trial design; however, bayesian trial design may provide a more optimal study technique for trauma-related studies. Objective To describe the outcomes of bayesian statistical approaches using data from the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial. Design, Setting, and Participants This quality improvement study performed a post hoc bayesian analysis of the PROPPR Trial using multiple hierarchical models to assess the association of resuscitation strategy with mortality. The PROPPR Trial took place at 12 US level I trauma centers from August 2012 to December 2013. A total of 680 severely injured trauma patients who were anticipated to require large volume transfusions were included in the study. Data analysis for this quality improvement study was conducted from December 2021 and June 2022. Interventions In the PROPPR Trial, patients were randomized to receive a balanced transfusion (equal portions of plasma, platelets, and red blood cells [1:1:1]) vs a red blood cell–heavy strategy (1:1:2) during their initial resuscitation. Main Outcomes and Measures Primary outcomes from the PROPPR trial included 24-hour and 30-day all-cause mortality using frequentist statistical methods. Bayesian methods were used to define the posterior probabilities associated with the resuscitation strategies at each of the original primary end points. Results Overall, 680 patients (546 [80.3%] male; median [IQR] age, 34 [24-51] years, 330 [48.5%] with penetrating injury; median [IQR] Injury Severity Score, 26 [17-41]; 591 [87.0%] with severe hemorrhage) were included in the original PROPPR Trial. Between the groups, no significant differences in mortality were originally detected at 24 hours (12.7% vs 17.0%; adjusted risk ratio [RR], 0.75 [95% CI, 0.52-1.08]; P = .12) or 30 days (22.4% vs 26.1%; adjusted RR, 0.86 [95% CI, 0.65-1.12]; P = .26). Using bayesian approaches, a 1:1:1 resuscitation was found to have a 93% (Bayes factor, 13.7; RR, 0.75 [95% credible interval, 0.45-1.11]) and 87% (Bayes factor, 6.56; RR, 0.82 [95% credible interval, 0.57-1.16]) probability of being superior to a 1:1:2 resuscitation with regards to 24-hour and 30-day mortality, respectively. Conclusions and Relevance In this quality improvement study, a post hoc bayesian analysis of the PROPPR Trial found evidence in support of mortality reduction with a balanced resuscitation strategy for patients in hemorrhagic shock. Bayesian statistical methods offer probability-based results capable of direct comparison between various interventions and should be considered for future studies assessing trauma-related outcomes.
Metabolomics as a tool to predict the risk of decompensation or liver-related death in patients with compensated cirrhosis
Authors: Oana Nicoară-Farcău, Juan J. Lozano, Cristina Alonso, Julia Sidorova, Càndid Villanueva, Augustín Albillos, Joan Genescà, Elba Llop, Jose L. Calleja, Carles Aracil, Rafael Bañares, Rosa Morillas, Maria Poca, Beatriz Peñas, Salvador Augustin, Marcel Tantău, Marcos Thompson, Valeria Perez-Campuzano, Anna Baiges, Fanny Turon, Virginia Hernández-Gea, Juan G. Abraldes, Edilmar A. Tapias, Ferran Torres, Jaime Bosch, Juan C. García-Pagán
Journal: Hepatology (2023)

Background and Aims: Patients with compensated cirrhosis with clinically significant portal hypertension (CSPH: HVPG &gt; 10 mm Hg) have a high risk of decompensation. HVPG is, however, an invasive procedure not available in all centers. The present study aims to assess whether metabolomics can improve the capacity of clinical models in predicting clinical outcomes in these compensated patients. Approach and Results: This is a nested study from the PREDESCI cohort (an RCT of nonselective beta-blockers vs. placebo in 201 patients with compensated cirrhosis and CSPH), including 167 patients for whom a blood sample was collected. A targeted metabolomic serum analysis, using ultra-high-performance liquid chromatography-mass spectrometry, was performed. Metabolites underwent univariate time-to-event cox regression analysis. Top-ranked metabolites were selected using Log-Rank p -value to generate a stepwise cox model. Comparison between models was done using DeLong test. Eighty-two patients with CSPH were randomized to nonselective beta-blockers and 85 to placebo. Thirty-three patients developed the main endpoint (decompensation/liver-related death). The model, including HVPG, Child-Pugh, and treatment received ( HVPG/Clinical model ), had a C-index of 0.748 (CI95% 0.664–0.827). The addition of 2 metabolites, ceramide (d18:1/22:0) and methionine (HVPG/Clinical/Metabolite model), significantly improved the model’s performance [C-index of 0.808 (CI95% 0.735–0.882); p =0.032]. The combination of these 2 metabolites together with Child-Pugh and the type of treatment received (Clinical/Metabolite model) had a C-index of 0.785 (CI95% 0.710–0.860), not significantly different from the HVPG-based models including or not metabolites. Conclusions: In patients with compensated cirrhosis and CSPH, metabolomics improves the capacity of clinical models and achieves similar predictive capacity than models including HVPG.
GJA1-20k Rescues Cx43 Localization and Arrhythmias in Arrhythmogenic Cardiomyopathy
Authors: Joseph A. Palatinus, Steven Valdez, Lindsey Taylor, Claire Whisenant, Craig H. Selzman, Stavros G Drakos, Ravi Ranjan, TingTing Hong, Jeffrey E. Saffitz, Robin M. Shaw
Journal: Circulation Research (2023)
Editor’s Choice – John Ingram – March 2023
Journal: British Journal of Dermatology (2023)

Youthful facial looks decrease the risk of age-related morbiditiesThis study taps into humankind's quest for eternal youth.Is appearing younger, in terms of perception of facial aging, associated with differences in parameters of health and internal morbidities?A cross-sectional population-based cohort study was performed using data from the Rotterdam Study.Facial photographs of 2679 men and women aged 51-87 years of European descent were assessed by a panel of men and women blinded to chronological age and medical history.Individuals perceived to look at least five years younger than their chronological age had lower rates of osteoporosis [odds ratio (OR) 0.76, 95% confidence interval (CI) 0.62-0.93],chronic obstructive pulmonary disease (OR 0.85, 95% CI 0.77-0.95),cataracts (OR 0.84, 95% CI 0.73-0.97)and age-related hearing loss, and better global cognitive functioning, after adjustment for confounders.So systemic and cognitive aging are, to an extent, externally visible on the human face and can be perceived by others.
Chromosome Fissions and Fusions Act as Barriers to Gene Flow between<i>Brenthis</i>Fritillary Butterflies
Authors: Alexander Mackintosh, Roger Vila, Dominik R Laetsch, Alex Hayward, Simon H Martin, Konrad Lohse
Journal: Molecular Biology and Evolution (2023)

Abstract Chromosome rearrangements are thought to promote reproductive isolation between incipient species. However, it is unclear how often, and under what conditions, fission and fusion rearrangements act as barriers to gene flow. Here we investigate speciation between two largely sympatric fritillary butterflies, Brenthis daphne and Brenthis ino. We use a composite likelihood approach to infer the demographic history of these species from whole-genome sequence data. We then compare chromosome-level genome assemblies of individuals from each species and identify a total of nine chromosome fissions and fusions. Finally, we fit a demographic model where effective population sizes and effective migration rate vary across the genome, allowing us to quantify the effects of chromosome rearrangements on reproductive isolation. We show that chromosomes involved in rearrangements experienced less effective migration since the onset of species divergence and that genomic regions near rearrangement points have a further reduction in effective migration rate. Our results suggest that the evolution of multiple rearrangements in the B. daphne and B. ino populations, including alternative fusions of the same chromosomes, have resulted in a reduction in gene flow. Although fission and fusion of chromosomes are unlikely to be the only processes that have led to speciation between these butterflies, this study shows that these rearrangements can directly promote reproductive isolation and may be involved in speciation when karyotypes evolve quickly.
Ground Reaction Force and Moment Estimation through EMG Sensing Using Long Short-Term Memory Network during Posture Coordination
Authors: Sei-ichi Sakamoto, Yonatan Hutabarat, Dai Owaki, Mitsuhiro Hayashibe
Journal: Cyborg and Bionic Systems (2023)

Motion prediction based on kinematic information such as body segment displacement and joint angle has been widely studied. Because motions originate from forces, it is beneficial to estimate dynamic information, such as the ground reaction force (GRF), in addition to kinematic information for advanced motion prediction. In this study, we proposed a method to estimate GRF and ground reaction moment (GRM) from electromyography (EMG) in combination with and without an inertial measurement unit (IMU) sensor using a machine learning technique. A long short-term memory network, which is suitable for processing long time-span data, was constructed with EMG and IMU as input data to estimate GRF during posture control and stepping motion. The results demonstrate that the proposed method can provide the GRF estimation with a root mean square error (RMSE) of 8.22 ± 0.97% (mean ± SE) for the posture control motion and 11.17 ± 2.16% (mean ± SE) for the stepping motion. We could confirm that EMG input is essential especially when we need to predict both GRF and GRM with limited numbers of sensors attached under knees. In addition, we developed a GRF visualization system integrated with ongoing motion in a Unity environment. This system enabled the visualization of the GRF vector in 3-dimensional space and provides predictive motion direction based on the estimated GRF, which can be useful for human motion prediction with portable sensors.
Polygenic Scores and Onset of Major Mood or Psychotic Disorders Among Offspring of Affected Parents
Authors: Alyson Zwicker, Janice M. Fullerton, Niamh Mullins, Frances Rice, Danella M. Hafeman, Neeltje E.M. van Haren, Nikita Setiaman, John A. Merranko, Benjamin I. Goldstein, Alessandra G. Ferrera, Emma K. Stapp, Elena de la Serna, Dolores Moreno, Gisela Sugranyes, Sergio Mas Herrero, Gloria Roberts, Claudio Toma, Peter R. Schofield, Howard J. Edenberg, Holly C. Wilcox, Melvin G. McInnis, Victoria Powell, Lukas Propper, Eileen Denovan-Wright, Guy Rouleau, Josefina Castro-Fornieles, Manon H.J. Hillegers, Boris Birmaher, Anita Thapar, Philip B. Mitchell, Cathryn M. Lewis, Martin Alda, John I. Nurnberger, Rudolf Uher
Journal: American Journal of Psychiatry (2023)

Objective: Family history is an established risk factor for mental illness. The authors sought to investigate whether polygenic scores (PGSs) can complement family history to improve identification of risk for major mood and psychotic disorders. Methods: Eight cohorts were combined to create a sample of 1,884 participants ages 2–36 years, including 1,339 offspring of parents with mood or psychotic disorders, who were prospectively assessed with diagnostic interviews over an average of 5.1 years. PGSs were constructed for depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuroticism, subjective well-being, p factor, and height (as a negative control). Cox regression was used to test associations between PGSs, family history of major mental illness, and onsets of major mood and psychotic disorders. Results: There were 435 onsets of major mood and psychotic disorders across follow-up. PGSs for neuroticism (hazard ratio=1.23, 95% CI=1.12–1.36), schizophrenia (hazard ratio=1.15, 95% CI=1.04–1.26), depression (hazard ratio=1.11, 95% CI=1.01–1.22), ADHD (hazard ratio=1.10, 95% CI=1.00–1.21), subjective well-being (hazard ratio=0.90, 95% CI=0.82–0.99), and p factor (hazard ratio=1.14, 95% CI=1.04–1.26) were associated with onsets. After controlling for family history, neuroticism PGS remained significantly positively associated (hazard ratio=1.19, 95% CI=1.08–1.31) and subjective well-being PGS remained significantly negatively associated (hazard ratio=0.89, 95% CI=0.81–0.98) with onsets. Conclusions: Neuroticism and subjective well-being PGSs capture risk of major mood and psychotic disorders that is independent of family history, whereas PGSs for psychiatric illness provide limited predictive power when family history is known. Neuroticism and subjective well-being PGSs may complement family history in the early identification of persons at elevated risk.
Folate metabolism negatively regulates OAS-mediated antiviral innate immunity via ADAR3/endogenous dsRNA pathway
Authors: Jing Wu, Qiao You, Ruining Lyu, Yajie Qian, Hongji Tao, Fang Zhang, Yurong Cai, Na Jiang, Nan Zheng, Deyan Chen, Zhiwei Wu
Journal: Metabolism (2023)

Folate (FA) is an essential cofactor in the one-carbon (1C) metabolic pathway and participates in amino acid metabolism, purine and thymidylate synthesis, and DNA methylation. FA metabolism has been reported to play an important role in viral replications; however, the roles of FA metabolism in the antiviral innate immune response are unclear.To evaluate the potential regulatory role of FA metabolism in antiviral innate immune response, we establish the model of FA deficiency (FAD) in vitro and in vivo. The molecular and functional effects of FAD on 2'-5'-oligoadenylate synthetases (OAS)-associated antiviral innate immunity pathways were assessed; and the potential relationship between FA metabolism and the axis of adenosine deaminases acting on RNA 3 (ADAR3)/endogenous double-stranded RNA (dsRNA)/OAS was further explored in the present study, as well as the potential translatability of these findings in vivo.FA-free RPMI 1640 medium and FA-free feed were used to establish the model of FAD in vitro and in vivo. And FA and homocysteine (Hcy) concentrations in cell culture supernatants and serum were used for FAD model evaluation. Ribonucleoprotein immunoprecipitation assay was used to enrich endogenous dsRNA, and dot-blot was further used for quantitative analysis of endogenous dsRNA. Western-blot assay, RNA isolation and quantitative real-time PCR, immunofluorescence assay, and other molecular biology techniques were used for exploring the potential mechanisms.In this study, we observed that FA metabolism negatively regulated OAS-mediated antiviral innate immune response. Mechanistically, FAD induced ADAR3, which interacted with endogenous dsRNA, to inhibit deaminated adenosine (A) being converted into inosine (I), leading to the cytoplasmic accumulation of dsRNA. Furthermore, endogenous dsRNA accumulated in cytoplasm triggered the host immune activation, thus promoting the expression of OAS2 to suppress the replication of viruses. Additionally, injection of 8-Azaadenosine to experimental animals, an A-to-I editing inhibitor, efficiently enhanced OAS-mediated antiviral innate immune response to reduce the viral burden in vivo.Taken together, our present study provided a new perspective to illustrate a relationship between FA metabolism and the axis of ADAR3/endogenous dsRNA/OAS, and a new insight for the treatment of RNA viral infectious diseases by targeting the axis of ADAR3/endogenous dsRNA/OAS.
<scp>DTRMWXHS</scp>‐12, a novel Bruton tyrosine kinase inhibitor, in combination with everolimus and pomalidomide in patients with relapsed/refractory lymphomas: An open‐label, multicenter, phase 1a/1b study
Authors: Scott F. Huntington, Stephen J. Schuster, Wei Ding, Amber B. Koehler, Danielle M. Brander, Allison C. Rosenthal, Jose F. Leis, Han W. Tun, Muhamad Alhaj Moustafa, Madiha Iqbal, Wei He, Albert S. Kearney, Timothy P. McKinlay, Min Gui, Anthony R. Mato
Journal: American Journal of Hematology (2023)

Preclinical studies have shown augmented activity when combining Bruton tyrosine kinase inhibitors (BTKi) with inhibitors of mammalian target of rapamycin (mTOR) and immunomodulatory agents (IMiD). We conducted a phase 1, open-label study at five centers in USA to evaluate the safety of triplet BTKi/mTOR/IMiD therapy. Eligible patients were adults aged 18 years or older with relapsed/refractory CLL, B cell NHL, or Hodgkin lymphoma. Our dose escalation study used an accelerated titration design and moved sequentially from single agent BTKi (DTRMWXHS-12), doublet (DTRMWXHS-12 + everolimus), and then to triplet therapy (DTRMWXHS-12 + everolimus + pomalidomide). All drugs were dosed once daily on days 1-21 of each 28-day cycle. The primary goal was to establish the recommended phase 2 dose of the triplet combination. Between September 27, 2016, and July 24, 2019, a total of 32 patients with a median age of 70 years (range 46 to 94 years) were enrolled. No MTD was identified for monotherapy and the doublet combination. The MTD for the triplet combination was determined to be DTRMWXHS-12 200 mg + everolimus 5 mg + pomalidomide 2 mg. Responses across all studied cohorts were seen in 13 of 32 (41.9%). Combining DTRMWXHS-12 with everolimus and pomalidomide is tolerable and shows clinical activity. Additional trials could confirm benefit of this all-oral combination therapy for relapsed/refractory lymphomas.
Double-Blind Placebo-Controlled Study of Memantine in Trichotillomania and Skin-Picking Disorder
Authors: Jon E. Grant, Eve Chesivoir, Stephanie Valle, Dustin Ehsan, Samuel R Chamberlain
Journal: American Journal of Psychiatry (2023)

Objective: Trichotillomania and skin-picking disorder are underrecognized and often disabling conditions in which individuals repeatedly pull at their hair or pick at their skin, leading to noticeable hair loss or tissue damage. To date there is a severe paucity of evidence-based treatments for these conditions. In this study, the authors sought to determine whether memantine, a glutamate modulator, is more effective than placebo in reducing hair-pulling and skin-picking behavior. Methods: One hundred adults with trichotillomania or skin-picking disorder (86 women; mean age, 31.4 years [SD=10.2]) were enrolled in a double-blind trial of memantine (dosing range, 10–20 mg/day) or placebo for 8 weeks. Participants were assessed with measures of pulling and picking severity. Outcomes were examined using a linear mixed-effects model. The prespecified primary outcome measure was treatment-related change on the NIMH Trichotillomania Symptom Severity Scale, modified to include skin picking. Results: Compared with placebo, memantine treatment was associated with significant improvements in scores on the NIMH scale, Sheehan Disability Scale, and Clinical Global Impressions severity scale in terms of treatment-by-time interactions. At study endpoint, 60.5% of participants in the memantine group were "much or very much improved," compared with 8.3% in the placebo group (number needed to treat=1.9). Adverse events did not differ significantly between the treatment arms. Conclusions: This study found that memantine treatment resulted in statistically significant reductions in hair pulling and skin-picking symptoms compared with placebo, with relatively high efficacy (based on number needed to treat), and was well tolerated. The glutamate system may prove to be a beneficial target in the treatment of compulsive behaviors.
Author Correction: Prostate cancer therapy personalization via multi-modal deep learning on randomized phase III clinical trials
Authors: Andre Esteva, Jean Feng, Douwe van der Wal, Shih-Cheng Huang, Jeffry P. Simko, Sandy DeVries, Emmalyn Chen, Edward M. Schaeffer, Todd M. Morgan, Yilun Sun, Amirata Ghorbani, Nikhil Naik, Dhruv Nathawani, Richard Socher, Jeff M. Michalski, Mack Roach, Thomas M. Pisansky, Jedidiah M. Monson, Farah Naz, James Wallace, Michelle J. Ferguson, Jean-Paul Bahary, James Zou, Matthew Lungren, Serena Yeung, Ashley E. Ross, Michael Kucharczyk, Luis Souhami, Leslie Ballas, Christopher A. Peters, Sandy Liu, Alexander G. Balogh, Pamela D. Randolph-Jackson, David L. Schwartz, Michael R. Girvigian, Naoyuki G. Saito, Adam Raben, Rachel A. Rabinovitch, Khalil Katato, Howard M. Sandler, Phuoc T. Tran, Daniel E. Spratt, Stephanie Pugh, Felix Y. Feng, Osama Mohamad
Journal: npj Digital Medicine (2023)
DUB-ling down on the epigenetic regulation of cancer stem cells in glioblastoma
Authors: Erin E Mulkearns-Hubert, Justin D Lathia
Journal: Neuro-Oncology (2023)

Journal Article DUB-ling down on the epigenetic regulation of cancer stem cells in glioblastoma Get access Erin E Mulkearns-Hubert, Erin E Mulkearns-Hubert Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USADepartment of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Justin D Lathia Justin D Lathia Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USADepartment of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USARose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USACase Comprehensive Cancer Center, Cleveland, Ohio, USA Corresponding Author: Justin D. Lathia, PhD, Lerner Research Institute, 9500 Euclid Ave., NC10, Cleveland, OH 44195, USA (lathiaj@ccf.org). https://orcid.org/0000-0003-3168-7290 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 5, May 2023, Pages 854–856, https://doi.org/10.1093/neuonc/noad040 Published: 22 February 2023 Article history Published: 22 February 2023 Corrected and typeset: 11 March 2023
The waxy mutation in sorghum and other cereal grains reshapes the gut microbiome by reducing levels of multiple beneficial species
Authors: Qinnan Yang, Mallory Van Haute, Nate Korth, Scott Sattler, Devin Rose, Anthony Juritsch, Jing Shao, Kristin Beede, Robert Schmaltz, Jeff Price, John Toy, Amanda E. Ramer-Tait, Andrew K. Benson
Journal: Gut Microbes (2023)

Waxy starches from cereal grains contain >90% amylopectin due to naturally occurring mutations that block amylose biosynthesis. Waxy starches have unique organoleptic characteristics (e.g. sticky rice) as well as desirable physicochemical properties for food processing. Using isogenic pairs of wild type sorghum lines and their waxy derivatives, we studied the effects of waxy starches in the whole grain context on the human gut microbiome. In vitro fermentations with human stool microbiomes show that beneficial taxonomic and metabolic signatures driven by grain from wild type parental lines are lost in fermentations of grain from the waxy derivatives and the beneficial signatures can be restored by addition of resistant starch. These undesirable effects are conserved in fermentations of waxy maize, wheat, rice and millet. We also demonstrate that humanized gnotobiotic mice fed low fiber diets supplemented with 20% grain from isogenic pairs of waxy vs. wild type parental sorghum have significant differences in microbiome composition and show increased weight gain. We conclude that the benefits of waxy starches on food functionality can have unintended tradeoff effects on the gut microbiome and host physiology that could be particularly relevant in human populations consuming large amounts of waxy grains.